Etomidateis a commercially-available medicine used for general intravenous anesthesia for a long time. As it acts rapidly and lasts for a short time, etomidate is a desirable medicine inducing general intravenous anesthesia. Etomidate has a unique pharmacological action on cardiovascular stability, causing a minimal suppression on systematic circulation when compared with the other general anesthetic medicines. Therefore, etomidate is particularly suitable in operation for patients with cardiac dysfunction (Cotton J F, Anesthesiology 2009; 111: 240). At present, the anesthetic mechanism of etomidate has already been identified. It induces anesthetic effects mainly by its binding to central inhibitory receptor GABAA, making this receptor more sensitive to GABA. However, further researches have indicated that etomidate has an inhibitory action on synthesis of cortical hormone in the body; especially during a prolonged continuous infusion, the inhibitory action becomes more obvious (Husain S S, J Med Chem 2006; 49: 4818-4825). Self-synthesis of cortical hormone is an important anti-inflammatory factor, and thus this shortcoming is unfavorable for recovery of the post-operative patient. As the unfavorable effect is gradually verified by clinical investigation, its use has gradually decreased in frequency. The suppression of etomidate on adrenal cortex hormone is mainly caused by its inhibiting the activity of 11β-hydroxylase. This enzyme is critical for cortical hormone synthesis. This unfavorable effect of etomidate is related to the imidazole structure in the medicinal molecule, and one N atom in the imidazole ring can form complexation with topological iron atom, thus strengthening the binding of medicinal molecules to the enzyme molecules. Thus, 11β-hydroxylase is inhibited. Moreover, the ability of etomidate binding to 11β-hydroxylase is 100 times stronger than that binding to GABAA acceptor. These finding shave brought an challenge to the designing of the imidazole derivatives, which should have no or weaker ability of binding to 11β-hydroxylase (Zolle I M, J Med Chem 2008; 51: 2244-2253). Etomidate is mainly metabolized in the liver. Based on the metabolic investigation, a time/effect curve has been drawn concerned with therapeutic effect and adverse effect for the etomidate use (Forman S A, Anesthesiology 2011; 114(3): 695-707). This curve has indicated that after one intravenous bolus of etomidate 3 mg/kg, the minimal effective concentration of anesthetic effect is 110 ng/ml, and the time for the plasma medicine concentration maintaining above 3 mg/kg is only 8 min, while the minimal effective concentration of etomidate for inhibition of cortical hormone synthesis is 8 ng/ml, and the plasma medicine concentration maintaining above 8 ng/mL is up to 8 h. These findings have indicated that when the patients are given an anesthetic dosage of etomidate, the inhibitory action on cortical hormone synthesis will be kept for a longer time after a fast loss of anesthetic effects.
Therefore, to obtain a better imidazole-type general anesthetic medicine that does not inhibit cortical hormone synthesis but retains pharmacological activity of etomidate is very important.
Contents of the Invention
The present invention provides an N-substituted imidazole carboxylic ester chiral compound containing an ether side chain and provides its preparation and application.
According to the present invention, the N-substituted 1H-imidazole-5-carboxylate chiral compounds include the pharmaceutically-acceptable salts of the chiral compound. The structure of the N-substituted imidazole carboxylic ester chiral compound is shown in Formula (I), where the configuration of chiral carbon C* belongs to the R form.

The pharmaceutically-acceptable salts related to the N-substituted imidazole carboxylic ester chiral compound include the commonly-used salts in the field of pharmacy, such as hydrochloride, hydrobromide and trifluoroacetate.
This kind of salt compounds can be obtained by optical resolution of their enantiomers or by direct preparation. In the polar aprotic solvent and at the presence of base substance, the target compound (Formula (I)) can be produced by substitution reaction of N-substituted imidazole carboxylic acid chiral compound (Formula (II)) with halide (Formula (III)). In Formulas (I) and (II), the configuration of chiral carbon C* belongs to the R form, and X is halogen. The reaction process is as follows:
Based on the above-mentioned method, other preferable ways can be used separately or in combination, which are specified in the following:
The halogen is preferably Br or Cl; the reaction solvent is preferably DMF; the base is preferably an inorganic base, e.g., alkali metal hydroxides or carbonates.
The structure of the compound of Formula (I) contains a basic N atom capable of forming the pharmaceutically-acceptable salts. The Formula (I) compound obtained by the above-mentioned preparation method or other ways can be combined with pharmaceutically-acceptable acid radicals to obtain the corresponding salts.
Guided by the present invention, the results of the animal experiments have shown that the N-substituted imidazole carboxylic ester compound of Formula (I) and its salts can induce fast and reversible pharmacologic actions such as sedative-hypnotic and/or anesthetic effects. Compared with etomidate, the single administration of the compounds can maintain a shorter anesthetic time, a more short-acting anesthetic effect and a better palinesthesia. It also can obviously decrease the inhibition on adrenocortical hormone and produce rapid and full recovery of the post-operative patient. The potency and the safety range of the corresponding (9-optical isomer (IV) and racemate (V) of the Formula (I) compound are obviously inferior to those of the R-form Formula (I) compound (including the pharmaceutically-acceptable salts). Thus, the N-substituted imidazole carboxylic ester chiral compound and the pharmaceutically-acceptable salts have an obvious advantage when they are used in preparation of central inhibitory medicines, which can generate better sedative, hypnotic and/or anesthetic effects on animals or human beings via their intravenous or non-intravenous administration.

The above contents concerned with the present invention will be illustrated in detail by the following examples as shown in the figures. However, it should not be considered that the scope of the present invention is only limited to the following examples. Guided by the present invention, all the substitutions or modifications should be included in the scope of the present invention.